An opioid is widely used for serious acute pain and chronic pain. It is known that an opioid shows a strong analgesic effect and also exhibits undesirable effect such as analgesic tolerance, hyperalgesia, constipation, dependence, and drowsiness (The Medical Clinics of North America, 2007, Vol. 91, p. 199). Conventionally, as a main method for treating and/or preventing analgesic tolerance or hyperalgesia caused by an opioid, increase in the dose of the opioid, opioid rotation, change of administration route, or the like has been performed. However, the increase in the dose of the opioid has a problem that the side effects of the opioid itself such as constipation, nausea, drowsiness, respiratory depression, confusion, and immunosuppression also become severe, and the critical effectiveness is decreased from the overall viewpoint. Further, as for the opioid rotation or change of administration route, there are not a few cases where the option to be taken is limited due to the site of pain or the past history of a patient (for example, nephropathy, hepatopathy, etc.).
As a method for reducing the undesirable effect of an opioid such as dependence, for example, there are reports as described below: (1) Oxytrex (“The Journal of Pain”, 2005, Vol. 6, p. 392) or Embeda (“Annual Meeting of The American Society of Anesthesiologists”, 2007, Abstract A1370), both of which are a mixed preparation of an opioid and an ultra-low dose of an opioid antagonist, reduces opioid physical dependence as compared with the single administration of an opioid; (2) methylnaltrexone improve constipation induced by the administration of an opioid (“The Annals of Pharmacotherapy”, 2007, Vol. 41, p. 984); (3) aminoguanidine suppresses analgesic tolerance and physical dependence of morphine (“European Journal of Pharmacology”, 2006, Vol. 540, pp. 60-66); (4) finasteride suppresses analgesic tolerance and physical dependence of morphine (“Hormones and Behavior”, 2007, Vol. 51, p. 605); (5) an N-methyl-D-aspartic acid (NMDA) receptor antagonist suppresses analgesic tolerance and dependence of opioid (“Naunyn-Schmiedeberg's Archives of Pharmacology”, 2000, Vol. 361, p. 425; “The Clinical Journal of Pain”, 2000, Vol. 16, pp. S73-9); (6) a GM1 ganglioside inhibitor suppresses analgesic tolerance and physical dependence of morphine and the like (US 2004-0087607); (7) 3,7-dimethyl-1-propargylxanthine (DMPX), which is an adenosine receptor antagonist, suppresses psychological dependence of morphine (see Non-patent document 1); (8) DMPX suppresses psychological dependence of heroine (see Non-patent document 2 and Patent document 1); (9) 8-(3-chlorostyryl) caffeine (CSC) suppresses psychological dependence of morphine (see Non-patent document 3); (10) ZM241385, which is an adenosine receptor antagonist, affects an excitatory postsynaptic current induced by DAMGO, which is one of the opioid peptides (see Non-patent document 4); and (11) SCH59261 and CSC, both of which are an adenosine receptor antagonist, suppress physical dependence of morphine (see Non-patent document 8).
On the other hand, it is known that adenosine is widely distributed in the body and exhibits various physiological effects on the central nervous system, cardiac muscle, kidney, smooth muscle, and the like via its receptors (see Non-patent document 5).
For example, it is known that an adenosine A1 antagonist has defecation promoting activity (see Non-patent document 6). It is also known that the adenosine A2A receptors are involved particularly in the central nervous system, and an adenosine A2A receptor antagonist is known to be useful as a therapeutic agent for, for example, Parkinson's disease and the like (see Non-patent document 7). Further, a composition comprising an adenosine A2A receptor antagonist and an opioid for treating restless legs syndrome (RLS) and the like are also known (see Patent documents 2 and 3). Further, a method for alleviating chronic consumption of abused drugs such as ethanol or an opioid using an adenosine A2A receptor antagonist (see Patent documents 1 and 4), a method for treating a disease with chronic musculoskeletal pain (see Patent document 5) and the like are known. Furthermore, it is also known that an adenosine A2B receptor antagonist is useful as a therapeutic agent for constipation (see Patent document 6).
As a compound having an adenosine A2A receptor antagonistic activity, for example, compounds represented by the following formulae (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), (VIII), and the like are known (see Patent documents 7 to 13, and Non-patent documents 9 to 11).
